Cytochrome b5 reductase 2 suppresses tumor formation in nasopharyngeal carcinoma by attenuating angiogenesis

Abstract

BackgroundCytochrome b5 reductase 2 (CYB5R2) is a potential tumor suppressor that inhibits cell proliferation and motility in nasopharyngeal carcinoma (NPC). Inactivation of CYB5R2 is associated with lymph node metastasis in NPC. This study aimed to explore the mechanisms contributing to the anti-neoplastic effects of CYB5R2.MethodsPolymerase chain reaction (PCR) assays were used to analyze the transcription of 84 genes known to be involved in representative cancer pathways in the NPC cell line HONE1. NPC cell lines CNE2 and HONE1 were transiently transfected with CYB5R2, and data was validated by real-time PCR. A chick chorioallantoic membrane (CAM) embryo model was implanted with CYB5R2-expressing CNE2 and HONE1 cells to evaluate the effect of CYB5R2 on angiogenesis. An immunohistochemical assay of the CAM model was used to analyze the protein expression of vascular endothelial growth factor (VEGF).ResultsIn CYB5R2-transfected NPC cells, PCR assays revealed up-regulated mRNA levels of Fas cell surface death receptor (FAS), FBJ murine osteosarcoma viral oncogene homolog (FOS), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), integrin beta 3 (ITGB3), metastasis suppressor 1 (MTSS1), interferon beta 1 (IFNB1), and cyclin-dependent kinase inhibitor 2A (CDKN2A) and down-regulated levels of integrin beta 5 (ITGB5), insulin-like growth factor 1 (IGF1), TEK tyrosine kinase (TEK), transforming growth factor beta receptor 1 (TGFBR1), and VEGF. The angiogenesis in the CAM model implanted with CYB5R2-transfected NPC cells was inhibited. Down-regulation of VEGF by CYB5R2 in NPC cells was confirmed by immunohistochemical staining in the CAM model.ConclusionCYB5R2 up-regulates the expression of genes that negatively modulate angiogenesis in NPC cells and down-regulates the expression of VEGF to reduce angiogenesis, thereby suppressing tumor formation.

Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing

“…CYB5R2 has been identified as a tumor suppressor that is epigenetically regulated 46 . CYB5R2 negatively regulates vascular endothelial growth factor 47 which could contribute to its tumor suppressor activity. Furthermore, CYB5R2 is epigenetically regulated through promoter methylation 48 , associated with patient survival of glioblastoma, and functions in collagen maturation, immunoregulation via toll-like receptor pathways, and osmotic stress 49 .…”

Long non-coding RNA MEG3 inhibits neovascularization in diabetic retinopathy by regulating microRNA miR-6720-5p and cytochrome B5 reductase 2

“…Several studies have shown that CYB5R2 is under expressed in human DR [ 18 ]. In addition, Ming et al [ 17 ] found that CYB5R2 is involved in the regulation of angiogenesis. In this study, CYB5R2 was also shown to be downregulated in the serum of patients with DR. Functionally, the knockdown of CYB5R2 promoted proliferation, migration, and angiogenesis, while inhibited apoptosis of hRMECs.…”

“…VEGF is an important angiogenic factor in DR, and new evidence suggests that the VEGF antibody treatment may be a new therapy for DR [ 42 , 43 ]. Multiple analyses have also shown that both MEG3 and CYB5R2 have a regulatory effect on VEGF [ 12 , 17 ]. Therefore, future studies will focus on the role of VEGF in DR mediated by MEG3/miR-6720-5p/CYB5R2.…”

“…CYB5R2, a flavoprotein, is involved in many oxidation and reduction reactions [ 16 ]. It has been reported that CYB5R2 regulates angiogenesis-related genes, thereby reducing angiogenesis around tumors [ 17 ]. In DR, only one study revealed the downregulation of CYB5R2 through a multi-bioinformatics analysis based on integrated gene expression profile data; however, its mechanism and function have not been fully explored [ 18 ].…”

Microsomal reductase activity in patients with thyroid neoplasms

“…The information on the role of CYB5R in carcinogenesis is extremely poor and contradictory. The study [30] [31] demonstrate that CYB5R2 has an oncosuppressive effect due to the suppression of neoangiogenesis. Contrary data was obtained by the authors of [10], who proved the key role of CYB5R3 in extravasation and colonization of cancer cells after intravenous administration to mice.…”